Investigation into the tissue-protective effects of erythropoietin against cardio-renal syndrome

2012 Fiscal Year Final Research Report

• Project/Area Number: 23790608
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: TOBA Hiroe 京都薬科大学, 薬学部, 助教 (90351270)
• Project Period (FY): 2011 – 2012
• Keywords: 臨床薬理学 / 心腎連関

Research Abstract

CKD was induced by five-sixths or seventeen-eighteenths nephrectomy. Proteinuria and CCr were aggravated and plasma ADMA level was increased in accordance with the degree of nephrectomy. Endothelial-dependent vasodilation was blunted and macrophage infiltration, osteopontin expression, NADPH oxidase-derived superoxide production and ACE activity were increased in nephrectomized rat aortas. These changes are correlated with the degree of renal dysfunction. ADMA enhanced the NADPH oxidase activity in endothelial cells, which was inhibited by cotreatment with ACE inhibitor, captopril. ADMA induced vascular injury not only by inhibiting NOS but also by inducing oxidative stress via ACE activation in CKD. On the other hand, low dose of erythropoietin inhibits endothelial dysfunction and inflammation in CKD and diabetic rat aorta beyond hematopoiesis. Erythropoietin reversed the levels of phospho-Akt and eNOS protein and plasma NOx, which were reduced in 5/6Nx. Furthermore, erythropoietin wa s administered to NO synthase inhibitor (L-NAME, 0.7 mg/ml)-treated rats. Erythropoietin improved endothelium-dependent vasodilatation. Macrophage infiltration in L-NAME-treated rats was reduced by erythropoietin. Erythropoietin enhanced the levels of phospho-Akt, HO-1 and Cu/Zn-SOD protein. The increased NADPH oxidase-derived superoxide production in L-NAME-treated rat was suppressed by erythropoietin. Erythropoietin also induced SOCS1 overexpression. Cotreatment with STAT5 inhibitor cancelled erythropoietin-induced suppression in NADPH oxidase-derived superoxide production in angiotensinII-treated endothelial cells. In conclusion, erythropoietin exhibited vasoprotective effects via NO production through Akt pathway. In addition, erythropoietin improved vascular injury in L-NAME-treated rats by antioxidativeproperties. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation as its mechanisms. In conclusion, erythropoietin exerts vasoprotective effects in CKD rats beyond hematopoiesis.

Research Products

• [Journal Article] Endothelial dysfunction, macrophage infiltration and NADPH oxidase-dependent superoxide production were attenuated by erythropoietin instreptozotocin-induced diabetic rat aorta. (2013)
  • Author(s): Wang J, Toba H, Morita Y, Nakashima K, Noda K, Tian W, Kobara M, Nakata T
  • Journal Title: Pharmacology Volume: 91 Pages: 48-58
  • DOI: DOI:10.1159/000343963
  • Peer Reviewed
• [Journal Article] Erythropoietin attenuated vascular dysfunction and inflammation by inhibiting NADPH oxidase-derived superoxide production in nitric oxide synthase-inhibited hypertensive rat aorta. (2012)
  • Author(s): Toba H, Kojima Y, Wang J, Noda K, Wei T, Kobara M and Nakara T
  • Journal Title: Eur.J. Pharmacol. Volume: 691(1-3) Pages: 190-197
  • DOI: DOI:10.1016/j.ejphar.2012.07.018.
  • Peer Reviewed
• [Journal Article] Telmisartan inhibitsvascular dysfunction and inflammation via activation of peroxisomeproliferator-activated receptor-γ in subtotal nephrectomized rat. (2012)
  • Author(s): Toba H, Tojo C, Noda K, Kobara M andNakata T
  • Journal Title: Eur. J. Pharmacol. Volume: 685(1-3) Pages: 91-98
  • DOI: DOI:10.1016/j.ejphar.2012.01.026.
  • Peer Reviewed
• [Journal Article] Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophageinfiltration by increasing nitric oxide inhypertensive 5/6 nephrectomized rat aorta. (2011)
  • Author(s): Toba H, Morishita M, Tojo C, Nakano A, Oshima Y, Kojima Y, Yoshida M, Nakashima K, Wang J, Kobara M and Nakata T
  • Journal Title: Eur. J. Pharmacol. Volume: 656 Pages: 81-87
  • DOI: DOI:10.1016/j.ejphar.2011.01.043.
  • Peer Reviewed
• [Presentation] Erythropoietin treatment inhibited NADPHoxidase-derived superoxide production and endothelial dysfunction in nitric oxide synthase inhibitor-treated rat aorta (2012)
  • Author(s): Hiroe Toba, Yushi Kojima, Kazuki Ishimizu, Yuko Iwata, Yusuke Taira, Jiahong Wang, Kazuki Noda, Miyuki Kobara, Tetsuo Nakata
  • Organizer: 24th Scientific Meeting of the International Society of Hypertension
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2012-10-01
• [Presentation] Erythropoietin attenuated vascular dysfunction and inflammation by inhibiting NADPH oxidase-derived superoxide production in nitric oxide synthase-inhibitedhypertensive rat aorta (2012)
  • Author(s): Hiroe Toba, Yushi Kojima, Jiahong Wang, Kazuki Noda, Miyuki Kobara, Tetsuo Nakata
  • Organizer: 22nd European Meeting on Hypertension and Cardiovascular Protection
  • Place of Presentation: London, UK
  • Year and Date: 2012-04-29
• [Presentation] Vascular dysfunction and remodeling ocurred in accordance with renal impairment in nephrectomizedrats (2011)
  • Author(s): Hiroe Toba, Shoko Murata, Yuko Oshima, Yushi, Kojima, Kohei Nakashima, Kazuki Noda, Jiahong Wang, Miyuki Kobara, Tetsuo Nakata
  • Organizer: 21st European Meeting onHypertension
  • Place of Presentation: Millan, Italy
  • Year and Date: 2011-06-19
• [Presentation] Low dose oferythropoietin improved endothelial dysfunction and inflammation in 5/6 nephrectomized rat aorta beyond hematopoiesis (2011)
  • Author(s): Hiroe Toba, Kohei Nakashima, Yuko Oshima,Yushi Kojima, Chisato Tojo, Jiahong Wang, Miyuki Kobara, and Tetsuo Nakata
  • Organizer: The 75th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-20